With the proliferation of biomedical implants, there has been an interest in modifying the implant's surface with biocompatible materials, in order to allow for its integration with local tissue (Hetrick et al., 2006, Chem. Soc. Rev. 35:780-789). The implant surface should be biocompatible and/or bioactive, have the ability to prevent or reduce local inflammatory responses, and ideally prevent post-operation infection (Hezi-Yamit et al., 2009, J. Biomed. Mater. Res. A 90:133-141).
Neural prostheses generally make use of electrodes. Stimulating electrodes are widely used in cochlear implants and deep brain stimulation (DBS) to restore hearing and alleviate the symptoms of Parkinson's disease (PD). Recording electrodes are used to restore movement in patients paralyzed by head trauma, spinal cord trauma or neurodegenerative diseases, by reading neural signals from the brain and translating them into movement commands.
Infection and inflammation may affect the longevity and even cause failure of the electrodes. The infection rate for DBS is 9-10% (Williams et al., 2010, Lancet Neurol. 9:581-591; Weaver et al., 2009, JAMA 301:63-73). Recording electrodes normally fail weeks to months after implantation, mostly due to inflammation and resultant neuronal loss. Glial scar encapsulation, a typical inflammatory response of the tissue in the central nervous system, increases the stimulation threshold, with detrimental effects on both the tissue and the electrode (Winter et al., 2007, J. Biomed. Mater. Res. B Appl. Biomater. 81:551-563). Poor performance of recording electrodes presents an obstacle for the development of next generation DBS, wherein closed-loop would integrates the neural signal recording system as feedback so that the stimulus is delivered in reaction to the ongoing brain activity.
Approximately 1 million Americans live with PD, and 60,000 are diagnosed with PD each year. The economic impact of PD in the U.S. is estimated at $23 billion/year. There is no known cure or disease regression treatment for PD, and current treatments (DBS or medication) only manage symptoms. DBS, or DBS plus medication, is more effective than medication alone in improving patient self-reported quality of life (Williams et al., 2010, Lancet Neurol. 9:581-591; Weaver et al., 2009, JAMA 301:63-73). Recording electrodes could in principle be used for a paralyzed PD patient to regain movement functions.
Minocycline hydrochloride (MH) is a small molecule tetracycline antibiotic commonly used to treat inflammation and infection. MH is not only a potent neuroprotectant, but also a BMP (bone morphogenic protein) inhibitor, reducing hypertrophic scaring and even preventing restenosis after stent implantation (Hua et al., 2006, Brain Research 1090:172-181; Yrjanheikki et al., 1999, Proc. Natl. Acad. Sci. USA 96:13496-13500; Henry et al., 2007, Plast. Reconstr. Surg. 120:80-88; Pinney et al., 2003, J. Cardiovasc. Pharm. 42:469-476). MH has shown remarkable therapeutic potential in a variety of neural injuries and neurological disorders, including traumatic brain injury (TBI), spinal cord injury (SCI), stroke, intracerebral hemorrhage (ICH), Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), due to its anti-inflammatory, anti-oxidant, and anti-apoptotic properties.
MH, with its neuroprotective and anti-inflammatory properties, has great potential to reduce inflammation and neuronal loss around implanted neural electrodes, and improve their functionality and longevity. Local release of MH from coatings on neural prostheses would expose tissue at the implantation site to high local concentrations of MH (not achievable by systemic administration) and avoid the deleterious side effects from systemic exposure.
Unfortunately, use of MH is limited because systemic administration of a safe dose of MH cannot achieve sufficiently high local concentration of MH to be neuroprotective or inhibit neointima formation. For example, systemic administration of 200 mg of MH daily (equivalent to 3 mg/kg, standard human dose) results in only about 0.5 μg/mL MH in the cerebrospinal fluid (CSF) in human subjects (Maier et al., 2007, Neurobiol. Dis. 25:514-525), which is far below the level required for neuroprotection (10-75 μg/mL) (Hua et al., 2006, Brain Research 1090:172-181; Fagan et al., 2010, Stroke 41:469-476). A dosage of 70-100 mg/kg/d of MH is required for reducing neointima formation in rats; however this dosage is much higher than the standard human dosage of 3 mg/kg/d (equivalent to 200 mg/daily) and is accompanied by toxicity (Pinney et al., 2003, J Cardiovasc Pharmacol. 42:469-476).
Systemic administration of MH for 1-6 days reduces secondary injury and improves functional recovery in SCI animal models (Lee et al., 2003, J. Neurotrauma 20:1017-1027; Stirling et al., 2004, J. Neurosci. 24:2182-2190; Teng et al., 2004, Proc. Natl. Acad. Sci. USA 101:3071-3076; Wells et al., 2003, Brain 126:1628-1637; Yune et al., 2007, J. Neurosci. 27:7751-7761). However, the doses of MH used in these studies (45-90 mg/kg) were much higher than the standard human dose (3 mg/kg) (Xu et al., 2004, BMC Neurol. 4:7). Likewise, oral administration of MH increased the quality and longevity of chronic neural recordings and post-cochlear implants (Rennaker et al., 2007, J. Neural Eng. 4:L1-5), but only at doses far above the maximum normal dose. Taken together, these facts indicate that systemic administration of MH cannot achieve high local concentrations sufficient for neuroprotection, scar prevention, and hyperplasia minimization. In particular, local delivery of MH may expose neural cells at the injury site to high drug concentration, while avoiding the deleterious side effects from systemic exposure. Further, sustained delivery may render feasible long-term treatments for maximum efficacy.
Minocycline is unstable in aqueous solution, especially at body temperature. Therefore, there is a need to develop a drug delivery system capable of sustained release and stabilization of minocycline. Sustained release of MH using solid macroparticles or nanoparticles has been attempted. Solid macro- or nanoparticles may be fabricated using, for example, double emulsion to make hydrophobic particles, or precipitation of oppositely charged polyelectrolytes by electrostatic interactions. The former mechanism was used to fabricate PLGA macrospheres, while the latter mechanism was used to create polyion complex (PIC) micelles (Soliman et al., 2010, Macromol. Biosci. 10:278-288). However, the acidic degradation products of PLGA can reduce local tissue pH and subsequently elicit host inflammation (Liu H, et al., 2006, Int'l J. Nanomed. 1:541), and this may exacerbate secondary injury. In addition, PLGA microspheres or nanoparticles have very low entrapment efficiency for hydrophilic drugs such as MH. The highest entrapment efficiency for MH reported so far is only 1.92% (Kashi T, et al., Int'l J. Nanomed. 7:221-234).
When attempting long-term delivery as used in MH treatment, release kinetics are paramount. Zero-order release (i.e., a drug release rate independent of time) enables drug delivery to be matched with the local drug requirement and is useful in the area of stent design (Hetrick et al., 2006, Chem. Soc. Rev. 35:780-789; Hezi-Yamit et al., 2009, J. Biomed. Mater. Res. A 90:133-141). Short-term super-clinical dosages rapidly reach clinically relevant dosages and can control acute local response to the newly inserted stent, while long-term release prevents chronic responses. Similar “burst” doses of MH prevent damage caused by brain lesion (Hua et al., 2006, Brain Research 1090:172-181). Depending on the clinical usage and local tissue response, a tunable release kinetic may allow for optimal chronic delivery dosing that enhances efficacy and reduces side effects.
There is a need in the art for a novel drug delivery system that affords sustained release of a therapeutic agent directly to a target site in a subject, thereby circumventing the need for systemic administration of the therapeutic agent. There is also a need in the art for compositions and methods that effectively reduce infection and inflammation associated to a neural prosthesis implanted in a subject, thus improving prosthetic longevity and reducing infection rate in the subject. The present invention addresses this unmet need in the art.